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2-hydroxyglutaric aciduria causes progressive damage to the brain. Two types of this disorder are known: D-2-hydroxyglutaric aciduria and L-2-hydroxyglutaric aciduria.
The main features of D-2-hydroxyglutaric aciduria are developmental delay, seizures, weak muscle tone (hypotonia), and abnormalities in the largest part of the brain (the cerebrum), which controls many important functions such as muscle movement, speech, vision, thinking, emotion, and memory. Symptoms of D-2-hydroxyglutaric aciduria can be severe or mild. Onset of the severe form usually occurs before the age of 6 months. In addition to the main features of this disorder, signs and symptoms of the severe form usually include lack of energy (lethargy), episodes of vomiting, facial abnormalities such as a prominent forehead or very small lower jaw (micrognathia), vision problems, a weakened and enlarged heart (cardiomyopathy), and breathing abnormalities. Onset of the mild form of D-2-hydroxyglutaric aciduria typically occurs between ages 6 months and 3 years. Symptoms of this form are variable but usually include seizures and minor delays in development. In rare cases, symptoms are so mild that no abnormalities are noticed.
L-2-hydroxyglutaric aciduria also damages the brain, particularly the region involved in coordinating movements (the cerebellum). As a result, affected individuals have problems with balance and muscle coordination (ataxia). Additional signs and symptoms include mental retardation, seizures, impaired speech, short stature, and an unusually large head (macrocephaly). Typically, signs and symptoms of this disorder begin during infancy or early childhood. Symptoms of L-2-hydroxyglutaric aciduria usually progress slowly, but severe disability occurs by early adulthood. In some cases, the onset of symptoms is delayed until adolescence or adulthood, and the symptoms tend to be milder compared to cases that begin during infancy.
Combined D-2-hydroxyglutaric aciduria and L-2-hydroxyglutaric aciduria has been reported in a small number of infants. Signs and symptoms are severe and occur within the first month of life.
2-hydroxyglutaric aciduria is a rare disorder. Worldwide, about 100 cases of L-2-hydroxyglutaric aciduria have been reported, and about 75 cases of D-2-hydroxyglutaric aciduria have been described.
Mutations in the D2HGDH and L2HGDH genes cause 2-hydroxyglutaric aciduria.
The D2HGDH gene provides instructions for making the enzyme D-2-hydroxyglutarate dehydrogenase, which helps to break down a compound called D-2-hydroxyglutarate. D2HGDH mutations impair the enzyme activity of D-2-hydroxyglutarate dehydrogenase. As a result, D-2-hydroxyglutarate does not break down and accumulates in cells. Researchers believe that this accumulation is toxic and damages brain cells, leading to the signs and symptoms of D-2-hydroxyglutaric aciduria.
The L2HGDH gene provides instructions for the enzyme L-2-hydroxyglutarate dehydrogenase, which helps to break down a compound called L-2-hydroxyglutarate. L2HGDH mutations impair the enzyme activity of L-2-hydroxyglutarate dehydrogenase. As a result, L-2-hydroxyglutarate does not break down and accumulates in cells. Researchers believe that this accumulation is toxic and damages brain cells, leading to the signs and symptoms of L-2-hydroxyglutaric aciduria.
This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. Most often, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but do not show signs and symptoms of the condition.